Targeting key growth regulatory molecules in cancer cells has now proven to be an effective therapy for many different types of cancer. Disruption of key growth regulatory molecules may function alone or in combination with cytotoxic chemotherapy. In breast cancer, targeting of human epidermal growth factor receptor 2 (HER2) with trastuzumab has been an important advance. Trastuzumab works as a single agent and in combination with cytotoxic chemotherapy in both early stage and advanced breast cancer. Our laboratory, along with many others, has provided preclinical data demonstrating the value of the insulin-like growth factor (IGF) system as a target for cancer therapy. Recently, several drugs have been developed to target the type I IGF receptor (IGF1R) and some are now entering phase II clinical trials. We have shown that IGF1R and its related receptors regulate many aspects of breast cancer biology and signaling through this receptor system is complex. In order to optimize the use of this strategy as a cancer therapy, a deeper understanding of how the IGF system regulates the cancer phenotype must be understood. We hypothesize that a more complete definition of the IGF system signaling components will assist in the clinical development of anti-IGF therapies. To more fully define the IGF signaling system effectors, we propose to: 1) identify the signaling pathways downstream of IGF1R that couple its activation to specific breast cancer phenotypes, 2) determine the role of the insulin receptor (InsR) in breast cancer, and 3) define the mechanisms of resistance to anti-IGF1R therapy. The success of anti-growth factor receptor cancer therapies has established a new paradigm for treatment of malignancy. As anti-IGF system therapies are emerging as cancer treatments, our long term goal is to define the mechanisms of IGF action in cancer cells in order to inform clinical development of these drugs.